Computer Aided Drug Designing and Molecular Modeling Laboratory, Department of Bioinformatics, Alagappa University, Karaikudi, Tamil Nadu 630 004, India.
Computer Aided Drug Designing and Molecular Modeling Laboratory, Department of Bioinformatics, Alagappa University, Karaikudi, Tamil Nadu 630 004, India.
Comput Biol Chem. 2019 Feb;78:414-423. doi: 10.1016/j.compbiolchem.2018.12.016. Epub 2018 Dec 26.
Glutamate, a major neurotransmitter in the central nervous system of human, plays a crucial role in various neurological pathways by activating the ligand-gated ion channels such as mGluR and iGluR. Dysfunction of mGluR 5 can cause Alzheimer's disease, Parkinson's disease, epilepsy, depression, anxiety, etc. In the current study, we have developed the energetically optimized pharmacophore model to screen the eMolecules database having more than 6 million compounds with the help of reported cocrystal structure with 3-chloro-5-[6-(5-fluoropyridin-2 yl)pyrimidin-4-yl]benzonitrile (PDB ID: 5CGD). The obtained hits were docked into the allosteric site of the target and further validation of E-pharmacophore was done by enrichment calculations followed by the molecular dynamics simulations to analyze the specific amino acid interactions with the compound present in the allosteric site of the receptor.
谷氨酸是人类中枢神经系统中的一种主要神经递质，通过激活配体门控离子通道（如 mGluR 和 iGluR），在各种神经通路中发挥着关键作用。mGluR5 的功能障碍可导致阿尔茨海默病、帕金森病、癫痫、抑郁、焦虑等。在本研究中，我们开发了能量优化的药效团模型，借助与 3-氯-5-[6-(5-氟吡啶-2-基)嘧啶-4-基]苯甲腈（PDB ID：5CGD）的报道共晶结构，对 eMolecules 数据库中超过 600 万个化合物进行筛选。获得的命中化合物与靶标变构位点对接，并通过富集计算进一步验证 E-药效团，随后进行分子动力学模拟以分析与受体变构位点中化合物相互作用的特定氨基酸。
